Gliomas, primary brain tumors, are notoriously difficult to control and manage. Unlike secondary tumors that have metastasized to the brain or non-glial brain tumors, gliomas demonstrate a unique invasive ability, characterized by a lack of well-defined borders between cancerous tissue and healthy brain. Conventional therapies including surgery, chemotherapy, and radiation therapy, are often only partially effective or ineffective treatments due to the invasive nature of gliomas. Therefore, the prognosis of patients afflicted with gliomas is uniformly grim.
Not only is the prognosis often negative, but the diagnosis of gliomas is a difficult and costly process as well. Detection of brain tumors requires costly imaging equipment that is not readily available at all medical facilities, and confirmation of imaging results usually requires invasive and dangerous surgical sampling of the tumor.
The nature of the extracellular matrix (ECM) in the brain may play a role in the invasive capabilities of cancer cells. During normal development, the composition of the extracellular matrix of the brain changes dramatically. Cell proliferation, migration, neuronal and glial outgrowth and angiogenesis in the developing brain take place in a soluble matrix permissive to cell movement. In the mature, developed brain however, cell motility is markedly decreased to stabilize mature cell to cell interactions (Hockfield, 1990, Semin. Dev. Biol. 1:55-63).
The mechanisms employed by malignant tumors to invade the surrounding tissue in the developed brain differ remarkably. For example, some malignant cells are capable of producing their own ECM molecules, such as hyaluronic acid (HA), thereby changing the balance and structure of the neighboring environment (Delpech et al., 1997, International Journal of Cancer 72:942-948; Kosaki et al., 1999, Cancer Research, 59: 1141-1145; Turley, 1992, Cancer and Metastasis Reviews 11:21-30; Tzanakakis et al., 1997 Biochimie. 79: 323-332; Zetter, 1993, Seminars in Cancer Biology 4: 219-229). Additionally, tumor cells can alter their interactions with ECM molecules by changing the composition of their cellular receptors, for example, the upregulation of the HA binding molecules RHAMM and CD44 (Goldbrunner et al., 1999, Acta Neurochirurgica 141: 295-305; Hall and Turley, 1995, Journal of Neuro-Oncology 26: 221-229; Hall et al., 1995, Cell 82: 19-28; Merzak et al., 1994, Cancer Research 54: 3988-3992). Further, malignant cells can degrade the existing normal matrix by producing proteolytic enzymes to digest the surrounding ECM (Furcht et al., 1994, Laboratory Investigation 70: 781-783; Mignatti and Rifkin, 1993, Physiological Reviews 73: 161-195; Stetler-Stevenson et al., 1993, FASEB Journal 7: 1434-1441). While the mechanisms that facilitate the invasion of tumor cells into adjacent tissue are diverse, it is perhaps the ability of malignant tumors to modify the composition of the surrounding matrix, including the production and digestion of matrix molecules, that best characterizes the invasive phenotype.
The role of proteases in the invasive process has been demonstrated in tumors of almost every tissue type (Furcht et al., 1994, Laboratory Investigation 70: 781-783; Mignatti and Rifkin, 1993, Physiological Reviews 73: 161-195; Stetler-Stevenson et al., 1993, FASEB Journal 7: 1434-1441), and have been strongly implicated in the invasive properties of high grade gliomas (DeClerck et al., 1991, Cancer Research 51: 2151-2157; Mohanam et al., 1994, Journal of Neuro-Oncology 22: 153-160; Nakagawa et al., 1994, Journal of Neurosurgery 81: 69-77; Rao et al., 1993, Cancer Research 53: 2208-2211; Rao et al., 1994, Journal of Neuro-Oncology 18: 129-138; Vaithilingham et al., 1992, Journal of Neurosurgery 77: 595-600; Yamamoto et al., 1994, Journal of Neuro-Oncology 22: 139-151). A wealth of literature has demonstrated that matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, are highly upregulated in gliomas, and that inhibition of these proteases can decrease glioma invasiveness (Deryugina et al., 1997, Journal of Cell Science 110: 2473-2482; Forsyth et al., 1999, British Journal of Cancer 79: 1828-1835; Hamasuna et al., 1999, International Journal of Cancer 82: 274-281; Rao et al., 1996, Clinical and Experimental Metastasis 14: 12-18; Sawaya et al., 1996, Clinical and Experimental Metastasis 14: 35-42; Uhm et al., 1996, Clinical and Experimental Metastasis 14: 421-433; Nakagawa et al., 1994, Journal of Neurosurgery 81: 69-77; Rao et al., 1993, Cancer Research 53: 2208-2211; Rao et al., 1994, Journal of Neuro-Oncology 18: 129-138). However, clinical trials employing MMP inhibitors for the treatment of primary tumors have been disappointing due to serious and deleterious side effects (Heath and Grochow, 2000, Drugs 59: 1043-1055).
One of the brain ECM molecules that plays an important role in glioma invasiveness and tumor progression is brain-enriched hyaluronan binding (BEHAB) protein (Hockfield et al., 1997, U.S. Pat. No. 5,635,370). BEHAB is a member of the proteoglycan tandem-repeat family of proteins, and exists as a both a secreted and GPI-anchored protein with a hyaluronan binding domain (Jaworski et al., 1994, J. Cell Biol. 125: 495-509; Yamada et al., 1994, J. Biol. Chem 269:10119-10126; Seidenbecher et al., 1995, J. Biol. Chem. 270: 27206-27212). Recent studies have demonstrated that BEHAB is a brain specific protein that is down-regulated as development progresses in the human brain (Gary et al., 2000, Gene 256: 139-147). Importantly, BEHAB is upregulated about 700% in almost all adult human glioma samples assayed to date (Jaworski et al., 1996, Cancer Research, 56: 2293-2298, Gary et al., 2000, Gene 256: 139-147).
BEHAB cleavage plays a prominent role in the progression of glioma. Recent work by Matthews et al. (2000, J. Biol. Chem. 275: 22695-22703) demonstrated that BEHAB is cleaved between Glu395-Ser396 into 50 kDa and 90 kDa fragments by a metalloproteinase, but not by an MMP. Instead, BEHAB is cleaved by a member of the a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of metalloproteinases, specifically, ADAMTS4.
Unfortunately, due to deleterious side effects, traditional metalloproteinase inhibitors have proved to be an ineffective method for treating gliomas. Given the inherent risks of both diagnosing and treating gliomas with conventional techniques, and the failure of newer treatment regimens such as metalloproteinase inhibitors, there exists a long felt need for a method to both diagnose and treat primary central nervous system (CNS) tumors. The present invention meets this need.